CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 6, November/December 2010
AFRICA
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body weight and creatinine clearance making no difference to
the drug’s efficacy.’
When it came to safety, the results were similar, suggesting
that rivaroxaban is as safe as it is effective. Once again, the
subgroup analysis showed no outliers. Findings in respect of
key secondary outcomes were as follows: net clinical benefit –
2.9% for rivaroxaban vs 4.2% for enoxaparin plus warfarin; total
mortality – 2.2 vs 2.9%; cardiovascular events – 0.7 vs 0.8% and
liver complications – 0.1 vs 0.2%, respectively.
Summarising, Prof Buller concluded that the findings suggest
that rivaroxaban offers a single-drug approach for both acute and
long-term anticoagulation. It is non-inferior to enoxaparin plus
warfarin in respect of efficacy and safety, works consistently
across subgroups, and has no associated liver toxicity.
The Einstein Extension study evaluated rivaroxaban against
placebo. Patients were treated for an average of 249 days.
Symptomatic recurrent VTE occurred in 7.1% of patients on
placebo vs 1.3% on rivaroxaban. The figures were 5.2% and
0.8%, respectively, for recurrent DVT. The principal safety
outcome – recurrence of major bleeding – was of course, 0% for
placebo but only 0.7% for rivaroxaban.
Clinically relevant non-major bleeding did occur, however, in
5.4% of those treated with rivaroxaban, versus 1.2% of those on
placebo. This was a statistically significant finding. Prof Buller
underscored, therefore, that it is important to bear in mind that
rivaroxaban’s long-term efficacy advantage does come at a cost.
‘Rivaroxaban brings about an 82% relative risk reduction in
the recurrence of VTE, he concluded, and it’s a simpler treatment
option. What is important is the need to consider very carefully
whether continued anticoagulation is indeed indicated.’
Clinical trials and bleeding – making sense of the
results
Prof Sylvia Haas, Technical University, Munich, Germany
Prof Haas spotlighted the many confounders that play a role in
the widely varying rates of major bleeding seen in hip and knee
arthroplasty trials. Among the factors that need to be considered
are: definition of what constitutes major bleeding; timing of
assessment of bleeding, whether pre or post surgery; timing of
administration of anticoagulants including the comparator agent
(enoxaparin), whether pre or early/late post surgery; dose and
duration of anticoagulation; and the collection of bleeding data
and adjudication of events. ‘And then there’s also the play of
chance’, she added.
There are therefore uncertainties and imponderabilities when
comparing bleeding rates across trials. When one looks at the
phase III trials of hip and knee replacements, one sees varying
definitions between trials and hence variance in the bleeding
rates from trial to trial. The bleeding rates in RE-NOVATE 1
and 2 (which evaluated dabigatran versus enoxaparin in total hip
replacement) differed because the comparator bleeding results
with enoxaparin at the same dose in each trial was different. The
adjudication of venograms may be different between trials as
well, and are only standardised within a particular trial; therefore
across-trial comparisons are often not helpful or accurate.
She underscored that it was therefore important to only
compare what can be directly compared. A study by Huisman
et al
. (submitted for publication) pooled the dabigatran trials,
excluding RENOVATE 2, and proved non-inferiority of dabi-
gatran’s efficacy relative to that of enoxaparin, in respect of the
primary endpoints of symptomatic VTE and all-cause mortal-
ity. Similarly, in a pooled study of the RECORD trials, without
RECORD 2, that evaluated rivaroxiban relative to enoxaparin
with the same endpoints, it showed the clear-cut superiority of
rivaroxaban.
‘One RECORD trial on its own met the primary endpoint
criteria of superiority, but with the added value of the other two
trials, there was a highly significant result in favour of rivar-
oxaban’, Prof Haas said. She warned that meta-analyses don’t
necessarily provide proof but are primarily hypothesis generat-
ing, as those undertaking them usually don’t have access to the
source data.
Prof Haas and her team did, however, have access to the
source data when they undertook a pooled analysis of RECORD
1–4 (submitted for publication). ‘The authors have been able to
include almost all (98%) patient data’, she said. ‘The efficacy
results were highly statistically significant for rivaroxaban versus
enoxaparin. While the combined results initially disfavoured
rivaroxaban, when it came to major bleeding, the differences
disappeared when we looked at only the period when all patients
were on active study medication. There was also no statistical
difference in bleeding rates using this approach, regardless of
whether we applied the ISTH or EMEA definitions of major
bleeding’, she added.
Concluding, she gave the following take-home messages:
•
Objective assessment of bleeding in patients undergoing
surgery is a challenge, as there are just too many factors influ-
encing the rates of major bleeding.
•
Meta-analyses are helpful for hypothesis generation, but
much less so for providing confirmed results.
•
The increasing number of meta-analyses does not help solve
the problem.
•
Well-designed non-interventional studies could be more
important to assess bleeding rates in the real world.
Monitoring of direct coagulation inhibitors – the
way forward?
Prof Sylvia Haas, Technical University, Munich, Germany
Addressing what users of these new agents need to know in the
clinical setting, Prof Haas pointed out that indirect factor Xa
inhibitors such as fondaparinux interact with free factor Xa and
do not alter prothrombin time (PT) measurements and interpreta-
tion thereof. However, the direct factor Xa inhibitors rivaroxaban
and apixaban directly interact with the factor Xa molecule and
the prothrombinase complex, thereby influencing prothrombin
time and related measurements. ‘They interfere with INR reli-
ability and if you do this test and get INR values of between 2
and 4, you could think that the patient is fully anti-coagulated,
but this is not necessarily so’, she pointed out.
For rivaroxaban, PT is the most sensitive anti-coagulation test
as there is a concentration-dependent prolongation, but interpre-
tation depends on the specific reagents being used. Applying a
standard calibration curve to the PT test results allows for corre-
lation with the plasma concentrations of rivaroxaban.
6
Dabigatran, the direct thrombin inhibitor weakly influences
PT and strongly affects the partial thromboplastin time (PTT),
while only weakly affecting the INR measurement and interpre-
tation. ‘A new test, hemoclot, which is a diluted thrombin test,
